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The Biochemistry of Pyrimidine Base Catabolism: Why Understanding Physiolog & y : ry O t p s i e West, Biochem Physiol 2015, 4:2 n m A e c h c c e o i s DOI: 10.4172/2168-9652.1000e135 s B Biochemistry & Physiology: Open Access ISSN: 2168-9652 Editorial Open Access The Biochemistry of Pyrimidine Base Catabolism: Why Understanding the Cellular Recycling of Pyrimidine Bases is Important Thomas P West* Department of Biology and Microbiology, South Dakota State University, Brookings, SD 57007, USA Pyrimidine base catabolism usually involves either a reductive to understand pyrimidine base catabolism better, new approaches in pathway or an oxidative pathway with the former more prevalent in using 5-fluorouracil as a chemotherapeutic agent more effectively may humans as well as in plants, unicellular eukaryotes and bacteria [1- be developed and new industrial applications to produce β-amino acids 4]. The reductive pathway involves three enzymes which include and D-amino acids may result. dihydropyrimidine dehydrogenase (EC 1.3.1.2), dihydropyrimidinase References (EC 2.5.2.2) and β-ureidopropionase (EC 3.5.1.6) [2-4]. The importance 1. West TP, Traut TW, Shanley MS, O’Donovan GA (1985) A Salmonella of the catabolism of pyrimidine bases in humans is directly related typhimurium strain defective in uracil catabolism and beta-alanine synthesis. J to the use of 5-fluorouracil as a chemotherapeutic agent during the Gen Microbiol 131: 1083-1090. treatment of cancer [5,6]. Genetic deficiencies for any of the reductive 2. Nyhan WL (2005) Disorders of purine and pyrimidine metabolism. Mol Genet pathway enzyme activities also appear to result in problems for Metab 86: 25-33. those individuals affected [7,8]. The pyrimidine catabolic pathway is 3. Andersen G, Merico A, Björnberg O, Andersen B, Schnackerz KD, et al. thought to be also involved in the degradation of pyrimidine-based (2006) Catabolism of pyrimidines in yeast: a tool to understand degradation of antimicrobials. The initial enzyme dihydropyrimidine dehydrogenase anticancer drugs. Nucleosides Nucleotides Nucleic Acids 25: 991-996. is important to the effectiveness of 5-fluorouracil as a chemotherapeutic 4. West TP (2011) Pyrimidine base catabolism in species of Pseudomonas and agent [9]. If the activity of the dehydrogenase is reduced, the Burkholderia. Res J Microbiol 6: 172-181. toxicity of 5-fluorouracil can increase [5,9]. If 5-fluorouracil is 5. Schneider HB, Becker H (2004) Dehydropyrimidine dehydrogenase deficiency rapidly degraded by the dehydrogenase, less of the analogue will be in a cancer patient undergoing 5-fluorouracil chemotherapy. Anticancer Res available to halt cancerous cell growth. Genetic deficiencies of the 24: 1091-1092. dehydrogenase have been reported and result in the urinary excretion 6. Ito T (2009) Children’s toxicology from bench to bed--Liver injury (1): Drug- of uracil, dihydrouracil, thymine and dihydrothymine. Individuals with induced metabolic disturbance--toxicity of 5-FU for pyrimidine metabolic dihydropyrimidine dehydrogenase deficiency exhibit symptoms that disorders and pivalic acid for carnitine metabolism. J Toxicol Sci 34 Suppl 2: include mental retardation and seizures [7,8]. Genetic deficiency of SP217-222. the second reductive pathway enzyme dihydropyrimidinase in humans 7. Van Kuilenburg AB, Vreken P, Abeling NG, Bakker HD, Meinsma R, et al. (1999) results in the accumulation of dihydropyrimidine bases in the blood, Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Hum Genet 104: 1-9. cerebrospinal fluid and urine plus can lead to 5-fluorouracil toxicity [10,11]. This autosomal recessive disease results in mental retardation, 8. van Kuilenburg AB, Meijer J, Mul AN, Hennekam RC, Hoovers JM, et al. (2009) Analysis of severely affected patients with dihydropyrimidine dehydrogenase gastrointestinal problems and seizures [10]. Beyond the importance of deficiency reveals large intragenic rearrangements of DPYD and a de novo pyrimidine catabolism to cancer treatment, the second pathway enzyme interstitial deletion del(1)(p13.3p21.3). Hum Genet 125: 581-590. dihydropyrimidinase has been shown to degrade antiepileptic agents 9. van Kuilenburg AB, Meinsma R, van Gennip AH (2004) Pyrimidine degradation [12]. This enzyme usually also has the ability to hydrolyze hydantoins defects and severe 5-fluorouracil toxicity. Nucleosides Nucleotides Nucleic and this could prove vital in the development of large-scale bioreactor Acids 23: 1371-1375. systems for the inexpensive production of β-amino acids and D-amino 10. van Kuilenburg AB, Dobritzsch D, Meijer J, Meinsma R, Benoist JF, et al. acids [4]. Genetic deficiency for the third reductive pathway enzyme (2010) Dihydropyrimidinase deficiency: Phenotype, genotype and structural β-ureidopropionase has been reported in humans [13]. High levels of consequences in 17 patients. Biochim Biophys Acta 1802: 639-648. N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid have 11. van Kuilenburg AB, Meinsma R, Zonnenberg BA, Zoetekouw L, Baas F, et al. been detected in urine and plasma of those affected individuals [13]. (2003) Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity. Clin The individuals afflicted with this enzyme deficiency exhibit a number Cancer Res 9: 4363-4367. of neurological problems including intellectual disabilities, seizures and 12. Maguire JH, Dudley KH (1978) Partial purification and characterization of microcephaly [13]. The severity of the neurological symptoms appears dihydropyrimidinases from calf and rat liver. Drug Metab Dispos 6: 601-605. to be greater in human β-ureidopropionase deficiency than in human 13. van Kuilenburg AB, Dobritzsch D, Meijer J, Krumpel M, Selim LA, et al. (2012) dihydropyrimidine dehydrogenase or dihydropyrimidinase deficiency ß-ureidopropionase deficiency: phenotype, genotype and protein structural [13]. Patients with β-ureidopropionase deficiency did not exhibit consequences in 16 patients. Biochim Biophys Acta 1822: 1096-1108. the gastrointestinal problems observed in the dihydropyrimidinase deficient patients [10,13]. *Corresponding author: West TP, Department of Biology and Microbiology, Although the literature exploring pyrimidine base catabolism South Dakota State University, Box 2104A, Brookings, SD 57007, USA, Tel: (605) 688-5469; Fax: 605-688-6677; E-mail: [email protected] has made significant strides relative to better understanding the rate of pyrimidine base catabolism as it relates to cancer treatment using Received April 01, 2015; Accepted April 02, 2015; Published April 09, 2015 5-fluorouracil, further research is needed to better characterize Citation: West TP (2015) The Biochemistry of Pyrimidine Base Catabolism: Why the reductive pathway and its regulation in other organisms. The Understanding the Cellular Recycling of Pyrimidine Bases is Important. Biochem opportunity exists to compare how the reductive pathway of pyrimidine Physiol 4: e135. doi: 10.4172/2168-9652.1000e135 catabolism is regulated in diverse organisms. This should provide new Copyright: © 2015 West TP. This is an open-access article distributed under the insights into how the pathway is regulated at the level of transcription terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and and the level of enzyme activity. By taking advantage of this opportunity source are credited. Biochem Physiol ISSN: 2168-9652 BCP, an open access journal Volume 4 • Issue 2 • 1000e135.
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